Porphyrins bearing four different meso substituents are important building blocks for biomimetic and materials chemistry. The existing method for the synthesis of such ABCD-porphyrins is shown in Scheme 1. The porphyrin-forming reaction entails acid-catalyzed condensation of a dipyrromethane-1,9-dicarbinol (I)+a dipyrromethane (II), which is believed to proceed via a bilane-carbinol (III) and a porphyrinogen (IV) with competing formation of polypyrromethanes (V). Treatment of the reaction mixture with an oxidant gives the porphyrin (VI).1,26 The current method enables synthesis of ˜1 g quantities of variously substituted ABCD-porphyrins with low or no detectable scrambling.
In developing access to ABCD-porphyrins, we have attempted to meet the following criteria: (1) little or no scrambling at any stage of the synthesis, (2) limited reliance on chromatography, (3) scalable syntheses affording at least 1 g of porphyrin, (4) straightforward implementation in a reasonable period (e.g., <1 week), (5) broad scope in terms of ABCD substituents, and (6) good yield. These criteria have been met in part. The procedures for forming the dipyrromethane and elaborating the dipyrromethane to give the dipyrromethane-1,9-dicarbinol are reasonably well developed and meet all six of the objectives outlined above. However, the final porphyrin-forming step still presents a number of limitations.

The drawbacks of the porphyrin-forming procedure include: (1) low concentration (2.5 or 25 mM), (2) low yield (15-22%), and (3) requisite use of column chromatography to purify the porphyrin. Such drawbacks need to be overcome to facilitate large-scale syntheses. In this regard, a lengthy series of studies was carried out recently to identify improved conditions for the acid-catalyzed condensation of the dipyrromethane-1,9-dicarbinol (I)+a dipyrromethane (II).1 Although acid catalysis conditions were identified for carrying out the reaction at 25 mM, the highest yield is typically obtained at 2.5 mM reactants. Higher concentrations tend to give larger amounts of polymer owing to the well-known concentration dependence of the competition between cyclization and polymerization (III→IV or V). Moreover, the use of higher concentrations typically requires an increased concentration of acid, whereupon the risk of acid-induced scrambling also is increased. The difficulty in identifying further improvements to the conditions for the 2+2 condensation has made the development of new routes for constructing the porphyrin macrocycle difficult.